While an outline for the genetic changes responsible for malignancy is rapidly being developed, three major related areas remain relatively obscure: (1)\does the transformed phenotype result from genetic alterations in controlling sequences that lead to abnormal expression of c-onc genes or do changes in coding regions of c-onc genes result in an altered function of the protein? Or either? (2)\How do genetic alterations in c-onc genes arise? (3)\Once an altered genotype is generated, how does the effected gene product ultimately lead to the transformed phenotype? This research focuses mainly on these three general questions by pursuing in detail the following observations we have made: (1)\RSV transformation leads to the activation of about 1000 new transcription units. (2)\At least one chemical carcinogen (bromoacetaldehyde) reacts preferentially with S1 and DNase I hypersensitive sites in chromatin and supercoiled plasmids. (3)\Tropomyosin synthesis is turned off translationally in RSV-CEF. Additional experiments are designed to identify replication origins in normal and transformed cells; to identify genes and gene products that fully activate the partially activated globin genes in RSV-transformed fibroblasts; and to identify genes and gene products, suppressed after RSV transformation, that are required for myoblast differentiation. (X)